Skip to main content
SpringerLink
Log in

Past and Present Definitions of Epileptogenesis and Its Biomarkers

  • Review
  • Published:
Neurotherapeutics

Abstract

Descriptions of epileptic seizures and epilepsy date back to antiquity, and research into fundamental mechanisms of epilepsy in animal models, as well as patients, has been carried out for over a century. Studies of epileptogenesis, however, as distinct from ictogenesis, have been pursued for only a few decades, and antiepileptogenesis, the prevention of epilepsy or its progression, and the reversal of the epileptogenic process or cure, are relatively recent interests of the basic research community. The goal to develop antiepileptogenic interventions would be greatly facilitated by the identification of reliable biomarkers of epileptogenesis that could be used to create cost-effective, high-throughput screening models for potential antiepileptogenic compounds, as well as enrich patient populations and serve as surrogate endpoints for clinical trials. Without such biomarkers, the cost for clinical validation of antiepileptogenic interventions would be prohibitive. Epileptogenic mechanisms, antiepileptogenic interventions, and biomarkers are likely to be specific for the many different causes of epilepsy, which include genetic influences, cell loss and synaptic plasticity, malformations of cortical development, and autoimmune disorders, to name but a few. A high priority is currently being placed on investigations to elucidate fundamental mechanisms of epileptogenesis and identify biomarkers for specific models of human epilepsy, such as mesial temporal lobe epilepsy with hippocampal sclerosis, traumatic brain injury, and a variety of pediatric diseases, including tuberous sclerosis and West syndrome.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Kinnear Wilson JV, Reynolds EH. Texts and documents: Translation and analysis of a cuneiform text forming part of a Babylonian treatise on epilepsy. Med Hist 1990;34:185-198.

    Article  Google Scholar 

  2. Mishra SK. Concept of neurologic disorders in “Ayurveda” ancient Indian medical treatise (abstr). Neurology 1987;37(Suppl. 1):240.

    Google Scholar 

  3. Manyam BV. Epilepsy in ancient India. Epilepsia 1992;33:473-475.

    Article  PubMed  CAS  Google Scholar 

  4. Fritsch G, Hitzig E. Ueber die elektrische Erregbarkeit des Grosshirns, Berlin, n.d. [Reprinted from Reichert’s und de Bois Reymond’s Archiv, Heft 3], 1870.

  5. Taylor J (ed.). Selected writings of John Hughlings Jackson. Vol 1. Basic Books, New York, 1958.

    Google Scholar 

  6. Ferrier D. Experimental researches in cerebral physiology and pathology. The West Riding Lunatic Asylum Medical Reports 1873;3:30-96.

    Google Scholar 

  7. Macewen W. Tumour of the dura matter removed during life in a person affected with epilepsy. Glas Med J 1879;12:210.

    Google Scholar 

  8. Horsley V. Brain surgery. Br Med J 1886;2:670-675.

    Article  Google Scholar 

  9. Engel J Jr. The emergence of neurosurgical approaches to the treatment of epilepsy.In: Waxman S (eds) From neuroscience to neurology: neuroscience, molecular medicine, and the therapeutic transformation of neurology. Elsevier, Amsterdam, 2005, pp. 81-105.

    Chapter  Google Scholar 

  10. Penfield W, Jasper H. Epilepsy and the functional anatomy of the human brain. Little, Brown & Co., Boston, MA, 1954.

    Google Scholar 

  11. Openchowski P. Sur l'action localisee du froid, applique a la surface de la region corticale du cerveau. Comptes Rendus des Seances et Memoires de la Societe de Biologie, 7th Ser. 1883;4:38-43.

  12. Echlin FA. The supersensitivity of chronically “isolated” cerebral cortex as a mechanism in focal epilepsy. Electroencephalogr Clin Neurophysiol 1959;11:697-722.

    Article  PubMed  CAS  Google Scholar 

  13. Kopeloff LM. Chusid JG, Pacella BL, Kopeloff N. Experimental chronic epilepsy in the monkey: effect of ablation of contralateral precentral motor cortex. AMA Arch Neurol Psychiatry 1955;67:336-343.

    Article  Google Scholar 

  14. Lockard JS, Cangdon WC, DuCharme LL, Finch CA. Slow-speed EEG for chronic monitoring of clinical seizures in monkey model. Epilepsia 1980;21:325-334.

    Article  PubMed  CAS  Google Scholar 

  15. Li CL. Functional properties of cortical neurons with particular reference to synchronization. Electroenceph Clin Neurophysiol 1955;7:475-478.

    Article  PubMed  CAS  Google Scholar 

  16. Matsumoto H, Ajmone-Marsan C. Cortical cellular phenomena in experimental epilepsy: Ictal manifestations. Exp Neurol 1964;9:305-326.

    Article  PubMed  CAS  Google Scholar 

  17. Matsumoto H, Ajmone-Marsan C. Cortical cellular phenomena in experimental epilepsy: Interictal manifestations. Exp Neurol 1964;9:286-304.

    Article  PubMed  CAS  Google Scholar 

  18. Morrell F. Secondary epileptogenic lesions. Epilepsia 1959/60;1:538-560.

    Google Scholar 

  19. Goddard GV. Development of epileptic seizures through brain stimulation at low intensity. Nature 1967;214:1020-1023.

    Article  PubMed  CAS  Google Scholar 

  20. Wada JA (ed.). Kindling. Raven Press, New York, 1976.

    Google Scholar 

  21. Corcoran ME, Moshé SL (eds). Kindling 6. Springer Science, New York, 2005.

    Google Scholar 

  22. Stafstrom CE, Sutula JP. Models of epilepsy in the developing and adult brain: implications for neuroprotection. Epilepsy Behav 2005;7:S18-S24.

    Article  PubMed  Google Scholar 

  23. Turski WA, Cavalheiro EA, Calderazzo-Filho LS, Kleinrok Z, Czuczwar SJ, Turski L. Injections of picrotoxin and bicuculline into the amygdaloid complex of the rat: an electroencephalographic, behavioural and morphological analysis. Neuroscience 1985;14:37-53.

    Article  PubMed  CAS  Google Scholar 

  24. Turski WA, Cavalheiro EA, Schwarz M, Czuczwar SJ, Kleinrok Z, Turski L. Limbic seizures produced by pilocarpine in rats: behavioural, electroencephalographic and neuropathological study. Behav Brain Res 1983;9:315-335.

    Article  PubMed  CAS  Google Scholar 

  25. Schwarcz R, Zaczek R, Coyle JT. Microinjection of kainic acid into the rat hippocampus. Eur J Pharmacol 1978;50:209-220.

    Article  PubMed  CAS  Google Scholar 

  26. Ben-Ari Y, Lagowska J, Tremblay E, Le Gal La Salle G. A new model of focal status epilepticus: intra-amygdaloid application of kainic acid elicits repetitive secondarily generalized convulsive seizures. Brain Res 1970;163:176-179.

    Article  Google Scholar 

  27. McIntyre DC, Nathanson D, Edson N. A new model of partial status epilepticus based on kindling. Brain Res 1982;250:53-63.

    Article  PubMed  CAS  Google Scholar 

  28. Engel J Jr. Mesial temporal lobe epilepsy: What have we learned? Neuroscientist 2001;7:340-352.

    Article  PubMed  Google Scholar 

  29. Pitkänen A, McIntosh TK. Animal models of post-traumatic epilepsy. J Neurotrauma 2006;23:241-261.

    Article  PubMed  Google Scholar 

  30. Galanopoulou AS. Basic mechanisms of catastrophic epilepsy – overview from animal models. Brain Dev 2013;35:748-756.

    Article  PubMed  Google Scholar 

  31. Engel J Jr, Pedley TA (eds) Epilepsy: a comprehensive textbook, 2nd ed. Lippincott Williams & Wilkins, Philadelphia, PA, 2008.

    Google Scholar 

  32. Panayiotopoulos CP, Benbadis SR, Beran RG, et al. (eds) Atlas of epilepsies 1. Volumes 1, 2, 3. Springer, London, 2010.

    Google Scholar 

  33. Berg AT, Berkovic SF, Brodie MJ, et al. Revised terminology and concepts for organization of seizures and epilepsies: Report of the ILAE Commission on Classification and Terminology, 2005–2009. Epilepsia 2010;51:676–685.

    Article  PubMed  Google Scholar 

  34. Engel J Jr. Seizures and epilepsy, 2nd ed. Oxford University Press, Oxford, 2013.

    Book  Google Scholar 

  35. Pitkänen A. Therapeutic approaches to epileptogenesis—Hope on the horizon. Epilepsia 2010;51(Suppl. 3):2-17.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  36. Engel J Jr. Biomarkers in epilepsy. Biomarkers Med 2011;5:529-664.

    Article  Google Scholar 

  37. Simonato M, Löscher W, Cole AJ, et al. WONOEP XI Critical review and invited commentary. Finding a better drug for epilepsy: preclinical screening strategies and experimental trial design. Epilepsia 2012;53:1860-1867.

    Article  PubMed  Google Scholar 

  38. Engel J Jr, Pitkänen A, Loeb JA, et al. Epilepsy biomarkers. Epilepsia 2013;54(Suppl. 4):61-69.

    Article  PubMed  Google Scholar 

  39. Helbig I, Lowenstein DH. Genetics of the epilepsies: where are we and where are we going? Curr Opin Neurol 2013;26:179-185.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  40. Lemke JR, Lai D, Reinthaler EM, et al. Mutations in GRIN2A cause idiopathic focal epilepsy with rolandic spikes. Nat Genet 2013;45:1067-1072.

    Article  PubMed  CAS  Google Scholar 

  41. Helbig I, Scheffer IE, Mulley JC, et al. Navigating the channels and beyond: unraveling the genetics of the epilepsies. Lancet Neurol 2008;7:231-245.

    Article  PubMed  Google Scholar 

  42. Carvill GL, Regan BM, Yendle SC, et al. GRIN2A mutations cause epilepsy-aphasia spectrum disorders. Nat Genet 2013;45:1073-1076.

    Article  PubMed  CAS  Google Scholar 

  43. Carvill GL, Heavin SB, Yendle SC, et al. Targeted resequencing in epileptic encephalopathies identifies de novo mutations in CHD2 and SYNGAP1. Nat Genet 2013;45:825-830.

    Article  PubMed  CAS  Google Scholar 

  44. Epi4K Conortium; Epilepsy Phenome/Genome Project. De novo mutations in epileptic encephalopathies. Nature 2013;501:217-221.

    Article  CAS  Google Scholar 

  45. Lesca G, Rudolf G, Bruneau N, et al. GRIN2A mutations in acquired epileptic aphasia and related childhood focal epilepsies and encephalopathies with speech and language dysfunction. Nat Genet 2013;45:1061-1066.

    Article  PubMed  CAS  Google Scholar 

  46. Barcia G, Fleming MR, Deligniere A, et al. De novo gain-of-function KCNT1 channel mutations cause malignant migrating partial seizures of infancy. Nat Genet 2012;44:1255-1259.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  47. Argyropoulos A, Gilby KL, Hill-Yardin EL. Studying autism in rodent models: reconciling endophenotypes with comorbidities. Front Hum Neurosci 2013;7:417.

    Article  PubMed Central  PubMed  Google Scholar 

  48. Coppola A, Moshé SL. Animal models. Handb Clin Neurol 2012;107:63-98.

    Article  PubMed  Google Scholar 

  49. Lerche H, Shah M, Beck H, Noebels J, Johnston D, Vincent A. Ion channels in genetic and acquired forms of epilepsy. J Physiol 2013;591:753-764.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  50. Blümcke I, Thom M, Aronica E, et al. International consensus classification of hippocampal sclerosis in temporal lobe epilepsy: A Task Force report from the ILAE commission on Diagnostic Methods. Epilepsia 2013;54:1315-1329.

    Article  PubMed  Google Scholar 

  51. Kuzniecky RI, Jackson GD. Malformations of cortical development. In: J Engel Jr, TA Pedley (eds) Epilepsy: a comprehensive textbook, 2nd ed. Lippincott Williams & Wilkins, Philadelphia, PA, 2008, pp. 2575-2588.

    Google Scholar 

  52. Blümcke I, Thom M, Aronica E, et al. The clinicopathologic spectrum of focal cortical dysplasias: A Consensus classification proposed by an ad hoc Task Force of the ILAE Diagnostic Methods Commission. Epilepsia 2011;52:158-174.

    Article  PubMed Central  PubMed  Google Scholar 

  53. Wong M. Animal models of focal cortical dysplasia and tuberous sclerosis complex: recent progress toward clinical applications. Epilepsia 2009;50(Suppl. 9):34-44.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  54. Liu JS. Molecular genetics of neuronal migration disorders. Curr Neurol Neurosci Rep 2011;11:171-178.

    Article  PubMed  CAS  Google Scholar 

  55. Vezzani A, Rüegg S. Introduction. In A Vezzani, S Rüegg (eds) Proceedings of the First Meeting on Immunity and Inflammation in Epilepsy: Mechanistic Insights and Therapeutic Perspectives. Epilepsia 2011b;52(Suppl 3):1-4.

  56. Granata T, Cross H, Theodore W, Avanzini G. Immune-mediated epilepsies. Epilepsia 2011;52(Suppl. 3):5-11.

    Article  PubMed Central  PubMed  Google Scholar 

  57. Lehrmann E, Guidetti P, Löve A, Williamson J, Bertram EH, Schwarcz R. Glial activation precedes seizures and hippocampal neurodegeneration in measles virus-infected mice. Epilepsia 2008;49(Suppl. 2):13-23.

    Article  PubMed  Google Scholar 

  58. Stewart KA, Wilcox KS, Fujinami RS, White HS. Development of postinfection epilepsy after Theiler’s virus infection of C57BL/6 mice. J Neuropathol Exp Neurol 2010;69:1210-1219.

    Article  PubMed Central  PubMed  Google Scholar 

  59. Pitkanen A, Narkilahti S, Bezvenyuk Z, Haapalinna A, Nissinen J. Atipamezole, an alpha(2)-adrenoceptor antagonist, has disease modifying effects on epileptogenesis in rats. Epilepsy Res 2004;61:119-140.

    Article  PubMed  CAS  Google Scholar 

  60. Jung KH, Chu K, Lee ST, et al. Cyclooxygenase-2 inhibitor, celecoxib, inhibits the altered hippocampal neurogenesis with attenuation of spontaneous recurrent seizures following pilocarpine-induced status epilepticus. Neurobiol Dis 2006;23:237-46.

    Article  PubMed  CAS  Google Scholar 

  61. Lukasiuk K, Sliwa A. FK506 aggravates development and severity of disease in the rat model of temporal lobe epilepsy. In: 8th European Congress on Epileptology, 21–25 September 2008, Berlin, Germany.

  62. Fabene PF, Navarro Mora G, et al. A role for leukocyte-endothelial adhesion mechanisms in epilepsy. Nat Med 2008;14:1377-1383.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  63. Chu K, Jung KH, Lee ST, et al. Erythropoietin reduces epileptogenic processes following status epilepticus. Epilepsia 2008;49:1723-1732.

    Article  PubMed  CAS  Google Scholar 

  64. Holtman L, van Vliet EA, van Schaik R, Queiroz CM, Aronica E, Gorter JA. Effects of SC58236, a selective COX-2 inhibitor, on epileptogenesis and spontaneous seizures in a rat model for temporal lobe epilepsy. Epilepsy Res 2009;84:56-66.

    Article  PubMed  CAS  Google Scholar 

  65. Paradiso B, Marconi P, Zucchini S, et al. Localized delivery of fibroblast growth factor-2 and brain-derived neurotrophic factor reduces spontaneous seizures in an epilepsy model. Proc Natl Acad Sci U S A 2009;106:7191-7196.

    Article  PubMed Central  PubMed  Google Scholar 

  66. Zeng LH, Rensing NR, Wong M. The mammalian target of rapamycin signaling pathway mediated epileptogenesis in a model of temporal lobe epilepsy. J Neurosci 2009;29:6964-6972.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  67. Huang X, Zhang H, Yang J, et al. Pharmacological inhibition of the mammalian target of rapamycin pathway suppresses acquired epilepsy. Neurobiol Dis 2010;40:193-199.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  68. Buckmaster PS, Lew FH. Rapamycin suppresses mossy fiber sprouting but not seizure frequency in a mouse model of temporal lobe epilepsy. J Neurosci 2011;31:2337-2347.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  69. van Vliet EA, Forte G, Holtman L, et al. Inhibition of mammalian target of rapamycin reduces epileptogenesis and blood-brain barrier leakage but not microglia activation. Epilepsia 2012;53:1254-1263.

    Article  PubMed  CAS  Google Scholar 

  70. Sliwa A, Plucinska G, Bednarczyk J, Lukasiuk K. Post-treatment with rapamycin does not prevent epileptogenesis in the amygdala stimulation model of temporal lobe epilepsy. Neurosci Lett 2012;509:105-109.

    Article  PubMed  CAS  Google Scholar 

  71. Heng K, Haney MM, Buckmaster PS. High-dose rapamycin blocks mossy fiber sprouting but not seizures in a mouse model of temporal lobe epilepsy. Epilepsia 2013;54:1535-1541.

    Article  PubMed  CAS  Google Scholar 

  72. Brandt C, Nozadze M, Heuchert N, Rattka M, Loscher W. Disease-modifying effects of phenobarbital and the NKCC1 inhibitor bumetanide in the pilocarpine model of temporal lobe epilepsy. J Neurosci 2010;30:8602-8612.

    Article  PubMed  CAS  Google Scholar 

  73. Polascheck N, Bankstahl M, Loscher W. The COX-2 inhibitor parecoxib is neuroprotective but not antiepileptogenic in the pilocarpine model of temporal lobe epilepsy. Exp Neurol 2010;224:219-233.

    Article  PubMed  CAS  Google Scholar 

  74. Dudek FE, Pouliot WA, Rossi CA, Staley KJ. The effect of the cannabinoid-receptor antagonist, SR141716, on the early stage of kainate-induced epileptogenesis in the adult rat. Epilepsia 2010;51(Suppl. 3):126-130.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  75. McClelland S, Flynn C, Dubé C, et al. Neuron-restrictive silencer factor-mediated hyperpolarization-activated cyclic nucleotide gated channelopathy in experimental temporal lobe epilepsy. Ann Neurol 2011;70:454-464.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  76. Ma L, Cui XL, Wang Y, et al. Aspirin attenuates spontaneous recurrent seizures and inhibits hippocampal neuronal loss, mossy fiber sprouting and aberrant neurogenesis following pilocarpine-induced status epilepticus in rats. Brain Res 2012;1469:103-113.

    Article  PubMed  CAS  Google Scholar 

  77. Gao F, Liu Y, Li X, Wang Y, Wei D, Jiang W. Fingolimod (FTY720) inhibits neuroinflammation and attenuates spontaneous convulsions in lithium-pilocarpine induced status epilepticus in rat model. Pharmacol Biochem Behav 2012;103:187-196.

    Article  PubMed  CAS  Google Scholar 

  78. Rattka M, Brandt C, Löscher W. Do proconvulsants modify or halt epileptogenesis? Pentylenetetrazole is ineffective in two rat models of temporal lobe epilepsy. Eur J Neurosci 2012;6:2505-2520.

    Article  Google Scholar 

  79. Williams-Karnesky RL, Sandau US, et al. Epigenetic changes induced by adenosine augmentation therapy prevent epileptogenesis. J Clin Invest 2013;123:3552-3563.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  80. Noe FM, Polascheck N, Frigerio F, et al. Pharmacological blockade of IL-1β/IL-1 receptor type 1 axis during epileptogenesis provides neuroprotection in two rat models of temporal lobe epilepsy. Neurobiol Dis 2013;59:183-193.

    Article  PubMed  CAS  Google Scholar 

  81. Tchekalarova J, Petkova Z, Pechlivanova D, et al. Prophylactic treatment with melatonin after status epilepticus: effects on epileptogenesis, neuronal damage, and behavioral changes in a kainate model of temporal lobe epilepsy. Epilepsy Behav 2013;7:174-187.

    Article  Google Scholar 

  82. Liu G, Gu B, He XP, et al. Transient inhibition of TrkB kinase after status epilepticus prevents development of temporal lobe epilepsy. Neuron 2013;79:31-38.

    Article  PubMed  CAS  Google Scholar 

  83. Grabenstatter HL, Del Angel YC, Carlsen J, et al. The effect of STAT3 inhibition on status epilepticus and subsequent spontaneous seizures in the pilocarpine model of acquired epilepsy. Neurobiol Dis 2014;62:73–85.

    Article  PubMed  CAS  Google Scholar 

  84. Echegoyen J, Armstrong C, Morgan RJ, Soltesz I. Single application of a CB1 receptor antagonist rapidly following head injury prevents long-term hyperexcitability in a rat model. Epilepsy Res 2009;85:123-127.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  85. Chrzaszcz M, Venkatesan C, Dragisic T, Watterson DM, Wainwright MS. Minozac treatment prevents increased seizure susceptibility in a mouse "two-hit" model of closed skull traumatic brain injury and electroconvulsive shock-induced seizures. J Neurotrauma 2010;27:1283-1295.

    Article  PubMed Central  PubMed  Google Scholar 

  86. Schwartzkroin PA, Wenzel HJ, Lyeth BG, et al. Does ketogenic diet alter seizure sensitivity and cell loss following fluid percussion injury? Epilepsy Res 2010;92:74-84.

    Article  PubMed  CAS  Google Scholar 

  87. Atkins CM, Truettner JS, Lotocki G, et al. Post-traumatic seizure susceptibility is attenuated by hypothermia therapy. Eur J Neurosci 2010;32:1912-1920.

    Article  PubMed Central  PubMed  Google Scholar 

  88. Goodrich GS, Kabakov AY, Hameed MQ, Dhamne SC, Rosenberg PA, Rotenberg A. Ceftriaxone treatment after traumatic brain injury restores expression of the glutamate transporter, GLT-1, reduces regional gliosis, and reduces post-traumatic seizures in the rat. J Neurotrauma 2013;30:1434-1441.

    Article  PubMed  Google Scholar 

  89. Guo D, Zeng L, Brody DL, Wong M. Rapamycin attenuates the development of posttraumatic epilepsy in a mouse model of traumatic brain injury. PLoS One 2013;8:e64078.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  90. Chen K, Neu A, Howard AL, et al. Prevention of plasticity of endocannabinoid signaling inhibits persistent limbic hyperexcitability caused by developmental seizures. J Neurosci 2007;27:46-58.

    Article  PubMed  CAS  Google Scholar 

  91. Zeng LH, Xu L, Gutmann DH, Wong M. Rapamycin prevents epilepsy in a mouse model of tuberous sclerosis complex. Ann Neurol 2008;63:444-453.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  92. Zhou J, Blundell J, Ogawa S, et al. Pharmacological inhibition of mTORC1 suppresses anatomical, cellular, and behavioral abnormalities in neural-specific Pten knock-out mice. J Neurosci 2009;29:1773-1783.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  93. Ljungberg MC, Bhattacharjee MB, Lu Y, et al. Activation of mammalian target of rapamycin in cytomegalic neurons of human cortical dysplasia. Ann Neurol 2006;60:420-9.

    Article  PubMed  CAS  Google Scholar 

  94. Yan HD, Ji-qun C, Ishihara K, Nagayama T, Serikawa T, Sasa M. Separation of antiepileptogenic and antiseizure effects of levetiracetam in the spontaneously epileptic rat (SER). Epilepsia 2005;46:1170-1177.

    Article  PubMed  CAS  Google Scholar 

  95. Russo E, Citraro R, Scicchitano F, et al. Comparison of the antiepileptogenic effects of an early long-term treatment with ethosuximide or levetiracetam in a genetic animal model of absence epilepsy. Epilepsia 2010;51:1560-1569.

    Article  PubMed  CAS  Google Scholar 

  96. Russo E, Citraro R, Scicchitano F, et al. Effects of early long-term treatment with antiepileptic drugs on development of seizures and depressive-like behavior in a rat genetic absence epilepsy model. Epilepsia 2011;52:1341-1350.

    Article  PubMed  CAS  Google Scholar 

  97. Dedeurwaerdere S, Boon P, De Smedt T, et al. Chronic levetiracetam treatment early in life decreases epileptiform events in young GAERS, but does not prevent the expression of spike and wave discharges during adulthood. Seizure 2005;14:403-411.

    Article  PubMed  Google Scholar 

  98. Blumenfeld H, Klein JP, Schridde U, et al. Early treatment suppresses the development of spike-wave epilepsy in a rat model. Epilepsia 2008;49:400-409.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  99. Sarkisova KY, Kuznetsova GD, Kulikov MA, van Luijtelaar G. Spike-wave discharges are necessary for the expression of behavioral depression-like symptoms. Epilepsia 2010;51:146-160.

    Article  PubMed  CAS  Google Scholar 

  100. Dezsi G, Ozturk E, Stanic D, et al. Ethosuximide reduces epileptogenesis and behavioral comorbidity in the GAERS model of genetic generalized epilepsy. Epilepsia 2013;54:635-643.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  101. Russo E, Citraro R, Scicchitano F, Urzino A, Marra R, Rispoli V, De Sarro G. Vigabatrin has antiepileptogenic and antidepressant effects in an animal model of epilepsy and depression comorbidity. Behav Brain Res 2011;225:373-376.

    Article  PubMed  CAS  Google Scholar 

  102. Russo E, Citraro R, Donato G, et al. mTOR inhibition modulates epileptogenesis, seizures and depressive behavior in a genetic rat model of absence epilepsy. Neuropharmacology 2013;69:25-36.

    Article  PubMed  CAS  Google Scholar 

  103. Baraban SC. Emerging epilepsy models: insights from mice, flies, worms and fish. Curr Opin Neurol 2007;20:164-168.

    Article  PubMed  CAS  Google Scholar 

  104. Kozauer N, Katz R. Regulatory innovation and drug development for early-stage Alzheimer’s disease. N Engl J Med 2013;368:1169-1171.

    Article  PubMed  CAS  Google Scholar 

  105. Thomas L, Di Stefano AL, Ducray F. Predictive biomarkers in adult gliomas: the present and the future. Curr Opin Oncol 2013;25:689-694.

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

This work was supported, in part, by NIH Grants P01 NS-02808, U01 NS-15654, R01 NS-33310, and P20 NS-80181, CURE, the Epilepsy Therapy Project, the Epilepsy Foundation, and the Resnick Foundation (JE) and The Academy of Finland, The Sigrid Juselius Foundation, and COST Action BM1001 (AP). We thank Dr. Ingo Helbig for graciously preparing Table 3.

Required Author Forms

Disclosure forms provided by the author are available with the online version of this article.

Author information

Authors and Affiliations

  1. Department of Neurobiology, A. I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland

    Asla Pitkänen

  2. Department of Neurology, Kuopio University Hospital, Kuopio, Finland

    Asla Pitkänen

  3. Department of Neurology, Neurobiology, and Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine at UCLA, 710 Westwood Plaza, Los Angeles, CA, 90095-1769, USA

    Jerome Engel Jr.

Authors
  1. Asla Pitkänen
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jerome Engel Jr.
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Jerome Engel Jr..

Electronic supplementary material

Below is the link to the electronic supplementary material.

ESM 1

(PDF 1224 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Pitkänen, A., Engel, J. Past and Present Definitions of Epileptogenesis and Its Biomarkers. Neurotherapeutics 11, 231–241 (2014). https://doi.org/10.1007/s13311-014-0257-2

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s13311-014-0257-2

Keywords

Search

Navigation